Application of Molecular Dynamics Simulations to the Design of Nucleotide Inhibitors Binding to Norovirus Polymerase.
J Chem Inf Model
; 60(12): 6566-6578, 2020 12 28.
Article
em En
| MEDLINE
| ID: mdl-33259199
ABSTRACT
The RNA-dependent RNA polymerase (RdRp) of norovirus is an attractive target of antiviral agents aimed at providing protection against norovirus-associated gastroenteritis. Here, we perform molecular dynamics simulations of the crystal structure of norovirus RdRp in complex with several known binders, as well as free-energy simulations by free-energy perturbation (FEP) to determine binding free energies of these molecules relative to the natural nucleotide substrates. We determine experimental EC50 values and nucleotide incorporation efficiencies for several of these compounds. Moreover, we investigate the mechanism of inhibition of some of these ligands. Using FEP, we screened a virtual nucleotide library with 121 elements for binding to the polymerase and successfully identified two novel chain terminators.
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Base de dados:
MEDLINE
Assunto principal:
Norovirus
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article